Dipyrromethanes have occupied a central place in porphyrin chemistry since the time of Hans Fischer. The dipyrromethane structures employed in the synthesis of naturally occurring porphyrins typically bear substituents at the β-positions and lack any substituent at the meso-position (Chart 1). In the past decade, meso-substituted dipyrromethanes lacking any β-substituents have come to play a valuable role in the preparation of synthetic porphyrins and related compounds such as dipyrrins and chlorins. A number of stepwise syntheses of dipyrromethanes lacking β-substituents have been developed,1 while more direct routes have employed one-flask condensations of pyrrole and the desired aldehyde.

The earliest one-flask synthesis entailed reaction of 4-pyridine carboxaldehyde with 2.1 molar equiv of pyrrole in methanol acidified with gaseous HCl, whereupon the corresponding 5-(4-pyridyl)dipyrromethane precipitated as the hydrochloride salt.2 In most applications such precipitation is not possible, in which case all excess of pyrrole is employed to suppress the continued reaction leading to linear and cyclic oligomers. A number of reports in the early-mid 1990s described methods where the aldehyde (0.04–0.5 M) was treated with excess pyrrole (2.1–40 molar equiv) in an acidified organic solvent: BF3-etherate/CH2Cl2,3 acetic acid/DMF4 or THF,5 SnCl4/CH2Cl2,6 p-toluenesulfonic acid/MeOH7,8 or toluene,9 or aq. HCl/THF.10 Workup typically entailed several steps including column chromatography, though Hammel et al. employed flash chromatography followed by Kugelrohr distillation.3 In 1994, we reported a method that employed the reaction of the aldehyde (0.34 M) dissolved in neat pyrrole (˜14 M) with no other solvent, relying on column chromatography for purification (“1994 procedure”).11 Catalysis was achieved at room temperature with TFA or BF3.O(Et)2, or in some cases12 upon heating without added acid. The reaction proceeded in a few minutes at room temperature and afforded the dipyrromethane in yields of ˜40–60%, but the use of chromatography for purification limited the scale.
Several groups have made modifications to the 1994 procedure. Both Boyle and we altered the workup protocol to facilitate preparative scale synthesis. Boyle employed flash chromatography to remove higher oligomers followed by Kugelrohr distillation, affording as much as ˜9 g of product.13-15 We examined the crude reaction mixture and found the dominant products to consist of the dipyrromethane, N-confused dipyrromethane, tripyrrane and other oligomers.16 We developed the following purification protocol: (1) aqueous base treatment and extraction with ethyl acetate; (2) removal of ethyl acetate and pyrrole; (3, optional) filtration through a pad of silica to remove high oligomers, which was typically done in cases where the crude products were especially discolored; (4) Kugelrohr distillation to give the dipyrromethane and N-confused dipyrromethane; and (5) recrystallization to remove the N-confused dipyrromethane. While this multistep purification protocol was effective for many aldehydes in small scale preparations, other aldehydes were too large or sensitive for distillation, requiring resort to chromatography. A few reports have appeared of the direct crystallization of the dipyrromethane from the reaction mixture, but given the complexity of the reaction mixture, direct crystallization appears to be viable only for selected aldehydes.17 
We sought to modify the conditions of the 1994 procedure such that the dipyrromethane could be isolated by crystallization from the crude reaction mixture. Our approach was guided by several observations. (1) Our prior analysis of the product distribution of the dipyrromethane-forming reaction employed GC and quantitated only the volatile products (dipyrromethane, N-confused dipyrromethane, and tripyrrane; ˜80%, 2–3%, and 15%, respectively, with TFA catalysis) of the reaction.16 However, TLC analysis of the crude reaction mixture showed the presence of “black material” at the origin, which was not analyzed by GC. Accordingly, the isolated yield of dipyrromethane generally fell significantly below the expected 85%. (2) We recently found that a wide variety of acid catalysts can be used in the pyrrole-aldehyde condensation leading to the porphyrinogen.18,19 We also found that several mild Lewis acids [InCl3, Sc(OTf)3, Dy(OTf)3, Yb(OTf)3] afford superior results compared with TFA in porphyrin syntheses via dipyrromethane-carbinols.20,21 Mild Lewis acids of this type have been found to have beneficial effects in diverse synthetic reactions.22 (3) In a few cases examined, a larger pyrrole:aldehyde ratio (e.g., 400:1) gave dipyrromethanes in yields of 90–95%.21,23 Accordingly, we began our studies by examining acids and pyrrole:aldehyde ratios that might afford less black material, which consumes starting material and complicates the purification procedure.
During the course of our work, two new methods were reported for carrying out the aldehyde-pyrrole condensation leading to dipyrromethanes: the use of ion exchange resins as acid catalysts,24 and the use of refluxing aqueous acid as a solvent for the reaction from which the dipyrromethane is obtained as a crystalline solid.25 The one-flask solventless synthesis approach also has found other applications, including (1) reaction of an aldehyde with excess furan or thiophene affording the difurylmethane or dithienylmethane, respectively;26 (2) reaction of excess pyrrole with a ketone affording a 5,5-dialkyldipyrromethane;27 and (3) reaction of excess pyrrole with an orthoester affording the corresponding tripyrromethane.28 Such reports illustrate the ongoing interest in efficient one-flask syntheses of dipyrromethanes.